KR100344477B1 - Carbamazepine medicament with retarded active substance release - Google Patents

Abstract

PCT No. PCT/DE95/00805 Sec. 371 Date Apr. 24, 1997 Sec. 102(e) Date Apr. 24, 1997 PCT Filed Jun. 22, 1995 PCT Pub. No. WO96/01112 PCT Pub. Date Jan. 18, 1996An oral administration carbamazepine medicament with a retarded active substance release is disclosed. An aqueous plasticised polymer dispersion is applied on carbamazepine crystals without causing formation of carbamazepine dihydrate. The carbamazepine crystals with their aqueous coating may be mixed with appropriate auxiliarly substances, shaped into divisible tablets or filled into capsules.

Description

Carbamazepine medicament with retarded active substance release}

The present invention relates to a process for the preparation of a carbamazepine medicament for delayed release of an active substance which can be administered orally. Carbamazepine, 5H-dibenz [b, f] azepine-5-carboxamide, is particularly used as an antiepileptic agent. Typical dosage forms are tablets with 200 mg of active substance or delayed release tablets with 200-600 mg of active substance and syrup.

Carbamazepine forms a dihydrate in the shortest time when contacted with water in a known manner. The dihydrate is formed by forming granules in a mixer or fluidized bed granulator using an aqueous liquid to form granules. These dihydrates are present in the form of acicular crystals that can increase the particle size to 500 μm. These have a negative effect on further processing, especially on the development of delayed release coatings. Because of this, known production methods give up an aqueous medium and prefer organic solvents. Delayed release of the active substance can be carried out in a variety of techniques and manners. Carbamazepine describes one formulation in German Patent No. 32 77 520, in which the active material is mixed with conventional tablet inerts and compressed into a core material or filled into capsules. The core material or capsule is coated using a methacrylic acid-methacrylic acid methylester mixture dissolved in isopropanol, containing acetyltributylcitrate as a softener. The use of an organic solvent prevents the formation of the dihydrate of carbamazepine. In German Patent No. 38 68 077 and German Patent No. 37 25 824, carbamazepine deactivator compositions containing protective colloids have been used, which inhibit the crystal growth of carbamazepine in the presence of water. Here, the core material containing carbamazepine is coated with an organic solution of cellulose acetate. Such membranes are formed in a suitable manner in the form of holes (holes).

The method of preparing such a formulation has a disadvantage of having to perform an operation using an organic solvent, which means that there is an environmental problem with the result and high cost and cost. In addition, the drug forms (tablets or capsules) prepared as mentioned above cannot be split because the shell is damaged upon splitting, thus losing the delayed release effect. Thus, the possibility of administration is reduced.

Other formulations (tablets) are known which do not lose their delayed release effect when divided or disintegrated into single particles in a liquid outside or inside the gastro-intestinal tract.

Solid oral formulations coated with an aqueous dispersion of copolymers of methacrylic acid and methylmethacrylic acid esters and compressed into tablets are described in Pharm. Ind. 55 . Nr. 10 (1993) S. 940-947. 25-50% of inert ingredients are added to disintegrate the tablet more quickly. Adding a softener significantly improves the elongation at break of the coating to ensure mechanical stability. In this connection mention is made of crystals of paraacetamol-, potassium chloride- and acetylsalicylic acid actives, theophylline granules and coating of indomethacin pellets and theophylline pellets.

The problem of the present invention is that despite the use of water as a solvent or dispersant, it is possible to use a carbamazepine agent which sufficiently inhibits the release of carbamazepine by interfering with crystal growth associated with the formation of the dihydrate by carbamazepine. will be.

This problem has been solved according to the present invention in which a film former combined with a softener is applied to the carbamazepine as an aqueous solution and / or dispersion. Coated carbamazepine can optionally be mixed with additional inert ingredients and compressed into tablets or filled into capsules.

Polyacrylate dispersions are used as film formers for delayed release of carbamazepine. Preferably it is as follows:

2: 1 ratio mixture of polyethyl acrylate and polymethyl methacrylate

(Eudragit NE 30D),

A mixture of 1: 2: 0.1 ratio of polyethylacrylate, polymethylmethacrylate and polymethylammonioethylmethacrylate chloride

(Eudragit RS 30 D) or

A mixture of 1: 2: 0.2 ratio of polyethylacrylate, polymethylmethacrylate and polymethylammonioethylmethacrylate chloride

(Eudragit RL 30 D)

As the water-soluble softener, for example, glycerol triacetate or triethyl citrate is discussed. They are used in a ratio of film former to softener 1: 0.05 to 1: 0.25, preferably 1: 0.15 to 1: 0.22.

The ratio of carbamazepine to membrane former is controlled for the desired delayed release effect and reaches from 1: 0.03 to 1: 0.5, in particular the ratio of carbamazepine to membrane former is from 1: 0.05 to 1: 0.1, preferably Is used from 1: 0.05 to 1: 0.08.

Use curves are shown in FIG. 1 for various ratios of such carbamazepine to membrane formers. The USP XXII dissolution test method for carbamazepine is used (medium: water containing 1% sodium dodecylsulfonate mineral).

Surprisingly, with the mixture of carbamazepine agents according to the invention, the formation of dihydrate spontaneously upon contact of water with carbamazepine and associated with the growth of needles in the form of needles, as is known, can be suppressed and thus poor Workability can be prevented.

In addition, the film formers combined with the softener are advantageously sprayed in the fluid bed granulator as aqueous solutions and / or dispersions. In addition, to prevent adhesion between the coated particles, a separator may be added to the membrane former dispersion and / or the separator may subsequently be sprayed onto the fluid phase as a separate suspension. For example, talc is added at a concentration ratio of membrane former to separator of 1: 0.4 to 1: 1, preferably 1: 0.45 to 1: 0.55.

Coated carbamazepine crystals can be mixed with additional galenic inerts in a known manner. The mixture or coated crystals so prepared can be filled into hard gelatin capsules or compressed into split tablets. The mentioned further processing of the coated carbamazepine, in particular the mechanical stresses on the individual particles involved in tableting, does not damage the membrane coating.

The final drug, when tested by the method of USP XXII for carbamazepine, shows the same dissolution rate delay as coated carbamazepine (see FIG. 2).

The method according to the invention is explained in more detail by the test examples.

Example 1

A suspension is prepared from 2.23 kg Eudragit RS 30 D, 135 g of glycerol triacetate dissolved in 1 l of water and 325 g of talc suspended in 1 l of water. This suspension is sprayed onto 10 kg of carbamazepine in a fluidized bed granulator WSG 15 (Glatt Company). Then a suspension of 625 g of talc in 2 liters of water is sprayed. The granules thus prepared are mixed with 914 g of microcrystalline cellulose, 653 g of insoluble polyvidone, 70 g of highly dispersed silicon dioxide and 35 g of magnesium stearate. The mixture is compressed into tablets with the active ingredient carbamazepine 200, 400 or 600 mg or the corresponding amount of granules is filled into size 1 capsules.

Example 2

A suspension is prepared from 340 g of Eudragit RS 30 D, 20.4 g of triethylcitrate dissolved in 0.3 L of water and 40 g of talc suspended in 0.1 L of water. This suspension is sprayed into 1 kg of carbamazepine at a manufacturing temperature of 27-30 ° C. in a flowable granulator GPCG 1 (Glatt Company). The granules thus prepared are mixed with 65 g of microcrystalline cellulose, 65 g of insoluble polyvidone, 7 g of highly dispersed silicon dioxide and 3.5 g of magnesium stearate. The mixture is compressed into tablets with the active ingredient carbamazepine 200, 400 or 600 mg or the corresponding amount of granules is filled into size 1 capsules.

Example 3

A suspension is prepared from 29 g of Eudragit NE 30 D, 1.3 g of glycerol triacetate dissolved in 0.03 L of water and 9 g of talc suspended in 0.03 L of water. This suspension is sprayed into 250 g of carbamazepine at a preparation temperature of 27 to 30 ° C. in a fluidized bed granulator UNI Glatt. The granules thus prepared are mixed with 16 g of microcrystalline cellulose, 16 g of insoluble polyvidone, 2 g of highly dispersed silicon dioxide and 1 g of magnesium stearate.

The mixture is compressed into tablets with the active ingredient carbamazepine 200, 400 or 600 mg or the corresponding amount of granules is filled into size 1 capsules.

Claims (14)

A method for preparing a carbamazepine agent, which delays the release of an active substance, characterized by spraying the carbamazepine in combination with an emollient and an aqueous solution or dispersion in a fluidized bed granulator. The method of claim 1, wherein the mixture of polyethyl acrylate and polymethyl methacrylate in a 2: 1 ratio and 1: 2 of polyethyl acrylate, polymethyl methacrylate and polytrimethylammonioethyl methacrylate chloride: A polymethacrylate mixture, which is a mixture of 0.1 or 1: 2: 0.2 ratio, is used as a film former. The method of claim 1 wherein the ratio of carbamazepine to membrane former is from 1: 0.03 to 1: 0.5. The method of claim 1 wherein the ratio of film former to softener is from 1: 0.05 to 1: 0.25. The method of claim 1 or 4, wherein the ratio of the film former to softener is from 1: 0.15 to 1: 0.22. 5. Process according to claim 1 or 4, characterized in that glycerol triacetate or triethyl citrate is used as a softener. The method according to claim 1, characterized in that the talc, which is a separating agent, is added to the membrane forming agent dispersion in a ratio of the membrane forming agent to the separating agent in a ratio of 1: 0.4 to 1: 1 or further sprayed in the fluid phase as a separate suspension. Way. The method of claim 1, wherein the coated carbamazepine is mixed with additional inerts and compressed into split tablets or filled into capsules. 8. The method of claim 1, wherein the coated carbamazepine is filled into capsules without mixing with additional inerts. 9. A method according to claim 5, characterized in that glycerol triacetate or triethyl citrate is used as a softener. 6. The method of claim 5, wherein the coated carbamazepine is mixed with additional inerts and compressed into split tablets or filled into capsules. 7. The method of claim 6, wherein the coated carbamazepine is mixed with additional inerts and compressed into split tablets or filled into capsules. 6. The method of claim 5, wherein the coated carbamazepine is filled into capsules without mixing with additional inerts. 7. The method of claim 6, wherein the coated carbamazepine is filled into capsules without mixing with additional inerts.